Neuroblastoma and medulloblastoma are common neuroectodermal tumors (NETs) of childhood. The tumor cells usually have molecular features of neuroblasts. Most neuroblastomas and a third of medulloblastomas express plasma membrane nerve growth factor (NGF) receptors (NGFR). Only a minority of NGFR + NET lines differentiate with NGF treatment, though NGF induces c-fos in many more. Recent studies indicate that c-fos is only one of a family of NGF-inducible transcription factors, and that a coordinated nuclear response to NGF, involving all these gene products, is required to initiate the changes in gene expression required for neuronal differentiation. Using model neuronal cell lines, we have shown that perturbation of any component of this immediate-early gene cascade can block NGF-induced differentiation. Based on these observations, we hypothesize that some human NETs arise because the immediate-early gene response to NGF in the tumor cells is incompetent to transactivate genes required for neuronal differentiation. To test this hypothesis, we plan a comprehensive analysis of the role of the Fos-Jun and Egr family of transcriptional factors in NGF-induced differentiation of human NET responses to NGF. These studies should permit a novel classification scheme for human NETs based on pathogenetic mechanisms, and may suggest avenues for improved therapy.